This application is in response to RFA-AA-07-019: Continuation of the Cooperative Agreement on the Interaction of HIV Infection and Alcohol Abuse on Central Nervous System Morbidity. The purpose is to evaluate the cumulative and progressive effects of combined HIV infection and alcohol abuse in vivo using advanced magnetic resonance imaging techniques to investigate the separate and interactive effects of chronic alcohol use and HIV infection on cognition and brain structural and functional integrity. Because hazardous alcohol use is a common problem among HIV infected individuals, it is important to study the additive and interactive effects of both conditions on brain structure and function. The long-term goal is to understand the mechanisms of the brain structural and cognitive decline in heavy drinking HIV-infected individuals to develop better treatments for these cognitive and neurological deficits. Over the past six years, we have evaluated the cumulative and progressive deleterious effects on the brain of combined alcohol abuse and HIV infection in an ethnically diverse community sample comprising four groups: high and low alcohol consuming HIV-infected subjects and high and low alcohol consuming HIV sero-negative subjects. One-year follow-up on 80% of the entry sample and three year follow-up on 75% have been completed. Cross-sectional analysis at study entry demonstrated substantial macrostructural, microstructural, and biochemical brain deficits in alcohol abusing patients with HIV infection, especially those whose disease had progressed to AIDS, compared with relative normality in asymptomatic HIV-infected patients. These findings are echoed in cognitive and motor performance and self-assessed quality of life. Longitudinal analyses of structural MRI indicate a prominent role for continued alcohol abuse in progressive brain damage, highlighting the need for detection and treatment of alcohol abuse in comorbid patients. In addition to the synergistic burden of alcohol abuse, the data also indicate significant effects of gender and self-identified ethnicity as important factors in detecting brain pathology. The objectives of the next five years of this program are to 1) establish the pattern of brain pathology with MR imaging and functional measures in an expanded sample of individuals with HIV infection and the combined morbidity of alcohol abuse;2) assess longitudinal HIV disease trajectory (progression or effective control) as modulated by alcohol abuse by continuing follow-up of the current cohort, testing them at 5 to 6 and 7 to 8 years after study entry;and 3) establish cross-sectional and longitudinal within-subject relationships among neuroimaging measures, cognitive and motor performance, and clinical status.